There is evidence that excessive neurohumoral activation may play a role in the progression of left ventricular (LV) failure. It has been shown that beta-blockers improve LV function and congestive heart failure symptoms in patients with dilated and ischemic cardiomyopathies. However, the mechanism by which beta-blockers improve heart failure is not well-understood. We hypothesized that beta blockers lead to improvement in LV function by increasing myocardial glucose utilization. Therefore, we compared LV ejection fraction (measured by radionuclide angiography) and fluorodeoxyglucose (FDG) uptake (measured by positron emission tomography) in 10 ischemic and nonischemic cardiomyopathy patients before and after 6 months of metoprolol therapy. All patients were NYHA class greater than or equal to II and on standard congestive heart failure medications prior to beta blockers. Improvement in LV function was pre-defined as an increase in LVEF of >7%. FDG uptake was normalized to the left ventricular sector with the highest blood flow on stress testing. At baseline, mean LVEF was 19% plus/minus 8%, mean plasma norepinephrine was 455 plus/minus 205 pg/ml and mean systolic blood pressure was 116 plus/minus 23 mmHg. After 6 months of beta blocker therapy, five patients (3 ischemic, 2 non-ischemic) had improved LVEF (from 22 plus/minus 10% before to 34 plus/minus 13% after therapy). LVEF in the remaining patients remained unchanged (from 14 plus/minus 6% before to 16% plus/minus 6% after therapy). There was a significant increase in FDG uptake in patients with improved LV function (0.87 plus/minus .23 to 0.96 plus/minus 0.34, p<0.01). In contrast, patients without improvement in LV function exhibited a significant decrease in FDG uptake (0.84 plus/minus 0.27 to 0.77 plus/minus 0.23, p<0.01). These preliminary findings indicate that improvement in LV function in heart failure patients treated with beta blockers is associated with increased glucose utilization. Both ischemic and non-ischemic cardiomyopathy patients demonstrate partial reversibility of LV dysfunction with beta blockers which may be mediated by an improvement in glucose metabolism.